In this Fast track SBIR grant we aim, by the end of Phase II, to prepare and commercialize a fully humanized rat with Knock-out of many rat drug metabolism related CYP450?s (9-in-9-out Rat Drug Metabolism-CYP450 Model) and Knock-in of the human counterpart. IN PHASE I we will develop an Active Genes: Gene Drive (AG:GD) rat ? a rat with a properly configured Cas9 to power Active Genetics (AG); AND, we will prepare the first CYP450 Kout/Kin, CYP2E1. AG:GD is a new technology invented by Synbal?s founders which allows Super-Mendelian conversion to homozygosity; thus, it can dramatically accelerate development of models with multiple genetic changes. These kinds of animals can be quickly crossed, using Active Genetics into immuno-deficient or other rat strains useful in modeling oncology and other diseases. Thus, this proposal answers the request for non-mouse preclinical models to test therapeutics within animal models of disease. In Phase II we will prepare a fully humanized rat ready for sale to the pharmaceutical research community. Additionally, the demonstration of Active Genetics in the rat, is an entry point in other vertebrates, like dogs, pigs or monkeys and therefore it will have a huge implication on the future of toxicity and efficacy testing.